DNA methylation of intragenic CpG islands depends on their transcriptional activity during differentiation and disease
Open accessAbstract
Significance: The human genome contains ∼30,000 CpG islands (CGIs), long stretches (0.5–2 kb) of DNA with unusually elevated levels of CpG dinucleotides. Many occur at genes' promoters, and their DNA nearly always remains unmethylated. Conversely, intragenic CGIs are often, but not always, methylated, and thus inactive as internal promoters. The mechanisms underlying these contrasting patterns of CGI methylation are poorly understood. We show that methylation of intragenic CGIs is associated with transcription running across the island. Whether or not a particular intragenic CGI becomes methylated during development depends on its transcriptional activity relative to that of the gene within which it lies. Our findings explain how intragenic CGIs are epigenetically programmed in normal development and in human diseases, including malignancy.
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Gene bodies have high levels of DNA methylation across both MP and SP genes.
“Gene bodies have high levels of DNA methylation20,53, which we observed across both MP and SP genes”
From Alternative promoters in CpG depleted regions are prevalently associated with epigenetic misregulation of liver cancer transcriptomes (2023) · cites this paper as [53]
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High-Resolution Profiling of Histone Methylations in the Human Genome
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Landscape of transcription in human cells
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Stability and flexibility of epigenetic gene regulation in mammalian development
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“Many intragenic CGIs become methylated during development, and this often coincides with transcription of the gene within which they lie; typical examples are CGIs in imprinted genes and at the X inactivation center (6, 7).”
Ligtenberg, M. J. L., Kuiper, R. P., Chan, T. L., Goossens, M., Hebeda, K. M., Voorendt, M., Lee, T. Y. H., Bodmer, D., Hoenselaar, E., Hendriks-Cornelissen, S. J. B., et al. (2009) · Nature Genetics · doi:10.1038/ng.283 · Cited by 818 · see citing works
Intragenic DNA methylation prevents spurious transcription initiation
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Genomic profiling of DNA methyltransferases reveals a role for DNMT3B in genic methylation
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Nepal, C., & Andersen, J. B. (2023) · Nature Communications · doi:10.1038/s41467-023-38272-4 · Cited by 39 · see citing works
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- Authors
- Jeziorska, D. M., Murray, R. J. S., De Gobbi, M., Gaentzsch, R., Garrick, D., Ayyub, H., Chen, T., Li, E., Telenius, J., Lynch, M., Graham, B., Smith, A. J. H., Lund, J. N., Hughes, J. R., Higgs, D. R., & Tufarelli, C.
- Affiliations
- University of Oxford (GB)
- University of Nottingham (GB)
- Medical Research Council Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford University, Oxford OX3 9DS, United Kingdom;
- The University of Texas MD Anderson Cancer Center (US)
- China Novartis Institutes for BioMedical Research, Shanghai 201203, China;
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2017-08-21
- Volume
- 114
- Issue
- 36
- Pages
- E7526-E7535
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC5594649
- OpenAlex
- W2748203881
- Cited by
- 166
- References
- 6
- Citations by year
- 2026: 12 · 2025: 17 · 2024: 16 · 2023: 18 · 2022: 36 · 2021: 17 · 2020: 21 · 2019: 17 · 2018: 10 · 2017: 1 · 2012: 1
- FWCI
- 5.47
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Repository@Nottingham (University of Nottingham) (publishedVersion, other-oa)
- Edinburgh Research Explorer (University of Edinburgh) (acceptedVersion, other-oa)
- ePrints Soton (University of Southampton) (acceptedVersion)
- Repository@Nottingham (University of Nottingham) (submittedVersion, cc-by)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
- Figshare (submittedVersion, cc-by)
- Funders
- RCUK | Medical Research Council (4050189188, Capacity Building Award)
- Royal Society (DHRF - 8363)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Syndromes and Imprinting
- Keywords
- DNA methylation, gene body methylation, transcription, DNMT3B, chromatin modification, transcription initiation, cell differentiation, epigenetics, cancer, genome rearrangement, promoter CpG islands
- MeSH terms
- Animals, Cell Differentiation, Cell Line, Humans, Promoter Regions, Genetic, Transcription, Genetic, Genome, Human, Sequence Analysis, DNA, CpG Islands, DNA Methylation, Epigenesis, Genetic, Mice
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